Here, we will test the hypothesis that IgG antibody blood-brain barrier permeability will increase in response to elevated surface sialic acid levels. Increasing the blood-brain barrier permeability of antibodies is important because antibody drugs for Alzheimer's Disease and other neurodegenerative disorders remain largely outside the brain after administration. Increasing antibody concentrations in the brain will help the antibodies access their primary therapeutic targets and may also tap into new immune pathways that benefit patients. The project consists of two aims that each address a question below: (1) Does the average IgG blood-brain barrier permeability increase upon addition of IgG sialic acid? (2) Is the blood-brain barrier permeability specific for sialylated IgG higher than fo desiaylated IgG? Both aims will use in vitro blood-brain barrier models to ensure that blood-brain barrier permeability is measured in the absence of other influx and efflux pathways.
Aim 1 uses a standard radiolabelling methodology for IgG detection.
Aim 2 uses a glycan-specific Surface Plasmon Resonance method to specifically track IgG with surface exposed sialic acid or galactose moieties. Support for this hypothesis will open new avenues for antibody treatment of Alzheimer's Disease and other diseases of the central nervous system.
Antibodies used for Alzheimer's Disease treatment face the major hurdle of entering the brain. Our proposal aims to determine if an increase in sialic acid on the surface of antibodies will increase their ability to permeate through the blood-brain barrier. If the results support the hypothesis, surface sialic acid modulation would provide a straightforward control mechanism to optimize the concentration of antibodies in the brains of AD patients.
| Finke, John M; Ayres, Kari R; Brisbin, Ryan P et al. (2017) Antibody blood-brain barrier efflux is modulated by glycan modification. Biochim Biophys Acta Gen Subj 1861:2228-2239 |
| Ochocinska, Margaret J; Zlokovic, Berislav V; Searson, Peter C et al. (2017) NIH workshop report on the trans-agency blood-brain interface workshop 2016: exploring key challenges and opportunities associated with the blood, brain and their interface. Fluids Barriers CNS 14:12 |
